Towards a cure for all (part one)

Gus Cairns

Published: 09 February 2011

For the
first time, someone has been cured of HIV infection. It was a brutal and
expensive procedure but, as Gus Cairns reports,
in the first of a two-part feature on curing HIV infection, it may signal the
way to a cure for everyone.

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The Berlin patient

On 13 December, NAM’s website aidsmap.com published
a news story1 which, thanks largely to circulation on social media
like Facebook and Twitter, received 50 times the usual hits.

It concerned the ‘Berlin
patient’, who we now know as Timothy Ray Brown, an American living in Berlin. He will go down
in history as the first person ever to be cured of HIV. His doctors had already
published two papers on his case2,3 (see HTU issues 182 and
192) but it was only in a third paper, summarising late results, that they
allowed themselves to say: “It is reasonable to conclude that cure of HIV
infection has been achieved in this patient.”4

The extraordinary explosion in interest hints
that, however well we are doing on our antiretrovirals (ARVs), however normal a
life people manage to live with HIV, most people still long to be rid of it.

Kill or cure

The cure Brown underwent was not one you’d
wish on anyone, though. It only happened because he developed something else:
leukaemia. This is cancer of the immune system, a wild overproliferation of the
blood cells originating in the bone marrow. When Brown’s chemotherapy failed
and his leukaemia returned, his doctors decided on the last resort - a bone
marrow transplant.

To do this, doctors destroy a large part of
the immune system to kill off the cancerous cells. They then introduce a graft
of bone marrow from a healthy donor who’s as closely matched genetically as
possible, so the host’s body doesn’t attack the new cells. These should then
become the patient’s new immune system.

What this also means, in a person with HIV,
is that if the original immune system is wiped out thoroughly enough, so are the
CD4 cells that harbour the virus.

Brown’s doctor, Gero Hütter, had an idea. He
knew that about 1% of Caucasians have a genetic mutation called the delta-32
double-delete mutation. ‘Double-delete’ means they inherited a copy of the same
defective gene from both parents. In these people, certain classes of immune
cell lack a cell-membrane protein called CCR5.

The majority of human immunodeficiency viruses,
and 99% of those transmitted, need to grab on to a CCR5 molecule in order to
infect a cell; indeed one of the newer HIV drugs, maraviroc (Celsentri),
works by blocking the CCR5 molecule.

People with this mutation are almost
completely resistant to HIV infection and, more importantly in this case, to
HIV proliferation: no CCR5 means no new cells to infect. So what would happen
if Brown’s immune system was replaced by one from a donor with no CCR5? Would
his HIV disappear?

To cut to the chase, the answer was yes, and
fast (for the full report, see www.aidsmap.com/page/1577949).
Despite being taken off ARVs the day before his bone marrow transplant, Brown
only had one more detectable viral load before it disappeared entirely. Two
months after his first transplant, all his bone marrow cells had become
CCR5-negative. Five months after, his CD4 cells were acting as if there was no
HIV in his body. At this point, however, the researchers could still find
CCR5-expressing cells in his gut, so they hesitated to announce a cure. Two
years later, they could find none anywhere, and the antibody responses which
define whether someone is ‘HIV-positive’ or not were dwindling away to
near-zero.

They also found no HIV in Brown’s brain. They
were certain of this because 17 months after his first transplant (he had to
have a second at 13 months), Brown developed a brain impairment and had a brain
biopsy. Hütter’s team can’t absolutely rule out this having been caused by a
flare-up of HIV lurking in the brain, but the biopsy and analysis of Brown’s
cerebrospinal fluid revealed no evidence of HIV. They suggest it was probably
due to immune deficiency caused by the transplant procedures and the
chemotherapy. He suffered temporary blindness, memory problems and loss of
muscular co-ordination.

“With Brown they used a more intense and
toxic regimen to prepare him for the transplant than is ever used in the United States,” says Johnston. “But even if all the procedural
details were worked out, you’d never find enough donors with the delta-32
mutation.”

Something along the lines of Brown’s cure has
been discussed since the dawn of the epidemic. One research paper6
documented 32 attempts between 1982 and 1996 to eradicate HIV using bone marrow
transplantation. In one in 1989,7 doctors succeeded in wiping out
HIV from the T-cells of a man dying of non-Hodgkin’s lymphoma within a month of
a bone marrow transplant from a negative donor. He died two weeks later of the
cancer, but autopsy specimens from brain, bone marrow, gut and other organs
could find no HIV.

The reason HIV is so hard to eradicate is
twofold. Firstly, a tiny proportion of cells infected with HIV become ‘resting
memory’ cells. These are cells whose job it is to stay secreted away in tissues
like the brain, lymph nodes and gut, like sleeper cells in a resistance
organisation, until a new infection comes along that resembles the one in which
they were originally created.

Secondly, ARVs seem to block most, but not
all, virus replication so there are still very low levels of virus replication
in patients on treatment – although its significance is an area of hot debate.

The problem with HIV is that one in every
thousand to every million resting memory cells is a double agent. Instead of
being equipped to fight HIV, it actually contains within its DNA, HIV’s genetic
code. As soon as you relax the police state enforced by ARVs, these cells set
off a whole new wave of infection.

Cells that produce virus soon die, but
putting people on ARVs means that the memory cells may never be activated. They
can lurk in the body life-long, as a ‘reservoir’ of HIV.

If you take someone off ARVs for a short
while, some reservoir cells die but other memory cells are infected, so you
just replenish the reservoir. This is why structured treatment interruptions
(‘drug holidays’) didn’t work.

Steven Deeks is professor of medicine at the
University of California. He puts it this way: “The
fundamental problem is that you’re trying to stimulate the output of part of
the immune system while dampening down another part.”

What we need is some fiendishly clever way
to get the HIV-infected lurking cells to come out of hiding and blow themselves
up, while at the same time protecting uninfected cells from infection.
They managed this with Brown – but only by replacing his immune system with
someone else’s.

Several other attempts to cure HIV didn’t
work either – although they may in the end contribute to a cure.

Very
early treatment. If you know someone has acute HIV,
within the first three weeks of infection, and give them ARVs right away, the
number of infected resting memory cells (the ‘reservoir’) is 10 to 100 times
less than in patients treated during chronic infection. In a few patients
treated like this, after stopping ARVs the viral load stayed low.8
In another study, however, HIV returned 50 days after therapy in a patient
treated early who only had one in every 1.7 billion resting memory cells
infected.9 In any case, this strategy would only work for the small
minority of people who test for HIV when they have acute infection.

Treatment
intensification. If you added more drugs to someone’s
ARV regimen, would it drive their viral load down to a point below which there
was too little HIV left for it to come back? A tall order if it requires fewer
than one in two billion cells to be infected, but there were high hopes when
the integrase inhibitor drug raltegravir (Isentress) came along, as it lowers
viral load faster than other drugs. A trial found, however, that it had no
significant effect on the residual replicating virus in the body.10
Similarly, maraviroc, the first drug of the CCR5 inhibitor class, failed to
drive viral load down to any useful extent when added to a regimen11
even though, as we have seen, CCR5 may hold the key to a cure.

Immune
stimulation. You can use cytokines (naturally occurring
immune modulators like IL-2 or IL-7) to activate resting cells to produce HIV
and destroy themselves. But IL-2 had no effect on the number of resting
infected cells,12 and the type of cells it stimulated do not replace
HIV-infected cells as a bone marrow transplant does. Also, IL-2 and IL-7 may
cause resting infected cells to divide and replenish the reservoir.13
Immune stimulant drugs can be very toxic: many patients found IL-2 hard to
tolerate and a previous study using IL-2 and another immune modifier called
OKT-3 left some in intensive care.14

Therapeutic
vaccine. Studies show that most of the minority of
people who control HIV without drugs have CD8 cells (the ones that kill
HIV-infected cells) with unusually high activity against HIV. You could try to
enhance CD8 cell responses with a therapeutic vaccine made from
immune-stimulating bits of HIV. But therapeutic vaccines by themselves have no
great record of success. They do seem to stimulate the anti-HIV activity of CD8
cells, but are ineffective at controlling HIV replication, probably because the
virus can mutate to evade the surveillance of the CD8 cells.15 If it
does, it can come back stronger than ever.16

And yet…the point about Timothy Ray Brown’s
cure is that, as Steven Deeks says, “For the first time ever, something worked.”

Rowena Johnston adds: “What’s important is
that it focused attention that an HIV cure is possible and realistic and that
this is a worthy research area to fund.”

So how might we cure HIV infection in ways
that are safer and less toxic than what happened to Brown? Clearly, if we knew,
we’d be doing it. But researchers are engaged in the early stages of a number
of promising strategies.

Gutiérrez
C et al. Effect of the intensification
with a CCR5 antagonist on the decay of the HIV-1 latent reservoir and residual
viremia. 17th Conference on Retroviruses and Opportunistic Infections San
Francisco, abstract 284, 2010.

Issue 203: January/February 2011

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